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Mycobacterium tuberculosis-infected human monocytes down-regulate microglial MMP-2 secretion in CNS tuberculosis via TNFα, NFκB, p38 and caspase 8 dependent pathways.

Green, JA; Dholakia, S; Janczar, K; Ong, CW; Moores, R; Fry, J; Elkington, PT; Roncaroli, F; Friedland, JS (2011) Mycobacterium tuberculosis-infected human monocytes down-regulate microglial MMP-2 secretion in CNS tuberculosis via TNFα, NFκB, p38 and caspase 8 dependent pathways. J Neuroinflammation, 8. p. 46. ISSN 1742-2094 https://doi.org/10.1186/1742-2094-8-46
SGUL Authors: Friedland, Jonathan Samuel

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Abstract

Tuberculosis (TB) of the central nervous system (CNS) is a deadly disease characterized by extensive tissue destruction, driven by molecules such as Matrix Metalloproteinase-2 (MMP-2) which targets CNS-specific substrates. In a simplified cellular model of CNS TB, we demonstrated that conditioned medium from Mycobacterium tuberculosis-infected primary human monocytes (CoMTb), but not direct infection, unexpectedly down-regulates constitutive microglial MMP-2 gene expression and secretion by 72.8% at 24 hours, sustained up to 96 hours (P < 0.01), dependent upon TNF-α. In human CNS TB brain biopsies but not controls the p38 pathway was activated in microglia/macrophages. Inhibition of the p38 MAP kinase pathway resulted in a 228% increase in MMP-2 secretion (P < 0.01). In contrast ERK MAP kinase inhibition further decreased MMP-2 secretion by 76.6% (P < 0.05). Inhibition of the NFκB pathway resulted in 301% higher MMP-2 secretion than CoMTb alone (P < 0.01). Caspase 8 restored MMP-2 secretion to basal levels. However, this caspase-dependent regulation of MMP-2 was independent of p38 and NFκB pathways; p38 phosphorylation was increased and p50/p65 NFκB nuclear trafficking unaffected by caspase 8 inhibition. In summary, suppression of microglial MMP-2 secretion by M.tb-infected monocyte-dependent networks paradoxically involves the pro-inflammatory mediators TNF-α, p38 MAP kinase and NFκB in addition to a novel caspase 8-dependent pathway.

Item Type: Article
Additional Information: © 2011 Green et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: Anti-Inflammatory Agents, Non-Steroidal, Caspase 8, Culture Media, Conditioned, Extracellular Signal-Regulated MAP Kinases, Humans, Matrix Metalloproteinase 2, Microglia, Monocytes, Mycobacterium tuberculosis, NF-kappa B, Sesquiterpenes, Signal Transduction, Tuberculosis, Central Nervous System, Tumor Necrosis Factor-alpha, p38 Mitogen-Activated Protein Kinases, Microglia, Monocytes, Humans, Mycobacterium tuberculosis, Tuberculosis, Central Nervous System, Sesquiterpenes, Extracellular Signal-Regulated MAP Kinases, p38 Mitogen-Activated Protein Kinases, Tumor Necrosis Factor-alpha, NF-kappa B, Anti-Inflammatory Agents, Non-Steroidal, Culture Media, Conditioned, Signal Transduction, Matrix Metalloproteinase 2, Caspase 8, Science & Technology, Life Sciences & Biomedicine, Immunology, Neurosciences, Neurosciences & Neurology, NERVOUS-SYSTEM TUBERCULOSIS, NECROSIS-FACTOR-ALPHA, METALLOPROTEINASE GENE-EXPRESSION, HUMAN CANCER-CELLS, MATRIX METALLOPROTEINASES, CEREBROSPINAL-FLUID, IN-VITRO, EPITHELIAL-CELLS, GELATINASE-B, IFN-GAMMA, 1103 Clinical Sciences, 1109 Neurosciences, 1107 Immunology, Neurology & Neurosurgery
Journal or Publication Title: J Neuroinflammation
ISSN: 1742-2094
Language: eng
Dates:
DateEvent
11 May 2011Published
11 May 2011Accepted
Publisher License: Creative Commons: Attribution 2.0
Projects:
Project IDFunderFunder ID
DHCS/06/05/012Department of Healthhttp://dx.doi.org/10.13039/501100000276
G0500385Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
UNSPECIFIEDWellcome Trusthttp://dx.doi.org/10.13039/100004440
PubMed ID: 21569377
Web of Science ID: WOS:000291591200001
Go to PubMed abstract
URI: http://openaccess.sgul.ac.uk/id/eprint/110609
Publisher's version: https://doi.org/10.1186/1742-2094-8-46

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